1. Field of the Invention
The invention relates to a process for the preparation of ortho-thioether-substituted aromatic ketones. More preferably, the invention relates a process of preparing an ortho-thioether-substituted aromatic ketone from a halonitroarene compound having a halo group ortho to a nitro group. Aromatic ketones are useful synthetic reagents for the preparation of both industrially important compounds such as herbicides and pharmaceutical compounds such as antihypertensive agents.
2. Description of the Related Art
Aromatic ketones are important synthetic intermediates for a number of valuable chemical compounds. For example, such compounds include isoxazole and isoxazole derivatives (Casado et al., WO 95/00476; and Cain et al., EP 470856). These compounds are useful herbicides. These types of ketones are normally prepared by the Friedel-Crafts acylation of an aromatic nucleus. However, in some cases this methodology does not produce the desired isomer, and more indirect methods must be employed.
Preparation of aromatic ketones via a nitroalkane displacement of a chloronitroarene followed by an oxidative Nef reaction has been previously reported. Such aromatic ketones are shown to be useful as synthetic intermediates in the preparation of antihypertensive agents.
Reid et al., Tetrahedron Lett. 31:1093 (1990). That preparation, however, utilizes the expensive base, diazabicyclo[2.2.1]undecene, for the displacement step. A similar reaction has been reported involving the displacement of 2,4-dinitrochlorobenzene by the lithium salt of 5-nitro-1,3-dioxane in DMSO solution. Kirillov et al., Zh. Org. Khim. 23:585 (1987). In this case, the nitronate salt was prepared and isolated in dry form from 5-nitro-1,3-dioxane and lithium methoxide in a separate reaction, a dangerous process due to the explosive nature of many alkanenitronate salts. Bretherick, L., Bretherick's Handbook of Reactive Chemical Hazards; Fourth Edition, Butterworths, London, 1693 (1990). This methodology is also not viable when using primary nitroalkanes unless additional base is used, since the displacement product is more acidic than the nitroalkane reactant. Unfortunately, the use of additional alkoxide base is not feasible either since commercially available alkoxide bases act primarily in a nucleophilic manner, affording as the major product the alkyl ether derived from aromatic nucleophilic displacement by the alkoxide.
The addition of nitromethane to nitroarenes using sodium hydroxide in dimethyl sulfoxide has been reported. Danikiewica et al., Tetrahedron Lett. 26:3599 (1985). This is a mechanistically different type of reaction than the nucleophilic aromatic substitution reaction, as it is an addition followed by aromatization (oxidation). The yields are quite low and the reaction works only with bicyclic nitroarene compounds and not with monocyclic nitroarene substrates.
Classic Nef reactions are performed by adding a solution of a nitronate anion to a strongly acidic aqueous solution. However, in many cases these conditions achieve only minimal conversion of the nitro group to the corresponding ketone, especially with a nitronate anion substituted on an aromatic ring. Conversion to the desired ketone can be achieved under oxidative Nef reaction conditions. However, a large excess of hydrogen peroxide, which is hazardous and economically unattractive, is necessary. Olah et al., Synthesis 662 (1980).
Phase-transfer catalyzed aromatic nucleophilic displacements by thiolates have been reported, but none of these involve aromatic nitro groups as the leaving group. EP 658544 (1995); Evans T.L., Synth. Commun. 14:435 (1984); Brunelle, D. J., J Org. Chem. 49:1309 (1984); Degani et al., Synthesis 630 (1983); Reeves et al., Synth. Commun. 12:1071 (1982); and Landini et al., J Org. Chem. 48:604 (1983).
Accordingly, there exists a need in the art for an efficient and cost-effective process for preparing aromatic ketones not accessible via classical Friedal-Crafts chemistry. There also exists a need for an efficient and cost-effective route to ortho-thioether-substituted aromatic ketones.